In order for multicellular organisms to function, it is necessary for the cells of a body to communicate with each other. In this way, it is possible to coordinate responses as required to constantly adjust to a continually changing external and internal environment 1!. This communication process is dependent on two operating systems, i.e., the nervous system in which signals or messages are transmitted, and hormones which are secreted and transported to adjacent or distant tissues. Both of these systems initiate specific physiological actions dependent on the particular type of cell that is activated.
The first step in the transmission of a brain signal is the synthesis of a chemical molecule called a neurotransmitter. Of the many brain neurotransmitters that have been identified, several are not synthesized de novo in nerve terminals, but rather are the result of a series of enzymatic reactions which modify a precursor molecule, usually an amino acid. After the molecules of the neurotransmitter have been biosynthesized, they are stored in the axon terminals of pre-synaptic nerve fibers in tiny membrane-bound sacs called synaptic vesicles which serve to protect the neurotransmitter molecules until they are used.
Serotonin is a neurotransmitter which the brain utilizes to send messages (electrical impulses) from one brain cell to another. Brain levels of serotonin have been shown to be involved in diverse physiologic processes, the most studied being sleep, appetite, mood, and pain threshold. Biochemical disturbances in the brain resulting in reduced levels of serotonin have been linked to insomnia 2!3!, excessive appetite and weight gain 4!5!, clinical depression, aggressiveness 6!7!8!, and lowered pain threshold 9!10!11!. The latter abnormality results in chronic, intractable pain that generally is refractory to treatment by conventional medications.
The neurotransmitter serotonin is synthesized in the brain from the amino acid L-.beta.-3. L-.beta.-3 cannot be made in the body. L-.beta.-3 must be introduced into the body from an outside source, such as from protein in food or as a dietary supplement. Along with the other amino acids present in the blood stream (which are absorbed from the small intestine from hydrolytic digestive processes in the gastrointestinal tract), L-.beta.-3 is carried to the brain. In the brain, a very selective process then takes place prior to the formation of serotonin.
In order for L-.beta.-3 to be converted to serotonin, L-.beta.-3 must first cross a separating mechanism that exists between the blood vessels in the brain and the brain proper. For L-.beta.-3 to pass from the circulating blood through the blood/brain barrier, a transport mechanism in the form of a carrier protein is required. The primary function of this mechanism is to isolate L-.beta.-3 from the majority of other amino acids circulating in the blood and, then, literally to transport L-.beta.-3 across this selective blood/brain barrier into the brain. There, a two-step enzymatic process converts the L-.beta.-3 first to 5-hydroxy-L-.beta.-3 and then to serotonin.
L-.beta.-3, however, is not the only amino acid carried by this transport mechanism. Five other amino acids, termed large neutral amino acids (LNAAs), are carried as well. LNAAs include phenylalanine, tyrosine, leucine, isoleucine, and valine. L-.beta.-3 not only has to compete with these LNAAs for access to the transport mechanisms, but L-.beta.-3 also has a lower affinity for the carrier system than do the LNAAs. Of the five LNAAs, phenylalanine is the most tightly bound to the transport protein and is therefore the most detrimental to the transport of L-.beta.-3 across the blood/brain barrier. To complicate this situation further, L-.beta.-3 in foods is present in lower amounts than the LNAAs, particularly in animal proteins. All of these factors converge to limit the amount of L-.beta.-3 that gets through to the brain to be finally converted into serotonin.
It is known that dietary supplementation with L-.beta.-3 increases the blood level of L-.beta.-3 and facilitates the passage of L-.beta.-3 across the blood/brain barrier into the brain. The increased amount of L-.beta.-3 in the brain permits a greater amount of L-.beta.-3 to be converted to serotonin. There are, however, numerous conditions that can interfere with and decrease the amount of L-.beta.-3 that normally passes through the blood/brain barrier into the brain each day. The primary factor that controls the degree to which L-.beta.-3 is transported across the blood/brain barrier is the ratio of L-.beta.-3 to LNAAs that is present in the blood going to the brain. At a lower-than-normal L-.beta.-3 to LNAA ratio, the number of molecules of L-.beta.-3 present at the blood/brain barrier is less than normal. The LNAAs, which are normally present in larger numbers than L-.beta.-3, then overwhelm the L-.beta.-3 by monopolizing the majority of the transport carriers, and even less L-.beta.-3 passes across the blood/brain barrier and into the brain as compared to the number of LNAAs that are passed across the barrier. In attempting to correct this improper L-.beta.-3/LNAA ratio, it was found that increasing dietary protein intake in order to add more L-.beta.-3 to the system can result, paradoxically, in an even greater derangement of the L-.beta.-3/LNAA ratio because of the simultaneous greater intake of LNAAs over the intake of L-.beta.-3.
One means by which the L-.beta.-3/LNAA ratio abnormality can be treated is by the administration of L-.beta.-3 without the accompanying presence of the LNAAs, especially without the presence of phenylalanine. This administration of L-.beta.-3 serves to increase the L-.beta.-3 portion of the circulating L-.beta.-3/LNAA ratio, increase the amount of L-.beta.-3 which will be transported across the blood/brain barrier into the brain, increase the L-.beta.-3 pool in the brain, and increase the rate of conversion of L-.beta.-3 to serotonin.
Prior to 1989, L-.beta.-3 was available to consumers as a dietary supplement and could be purchased freely. Studies on the oral administration of L-.beta.-3 under proper dietary conditions that provided a supplementary intake of this particular amino acid showed that supplemental L-.beta.-3 helped to correct an improper L-.beta.-3/LNAA ratio in the brain. This increased level of brain L-.beta.-3 directly produced an increased brain serotonin level which was associated with a reduction or elimination of serotonin-deficiency syndromes.
In the late 1980's, none of the L-.beta.-3 available in nationally-marketed preparations was produced in the United States. All of the L-.beta.-3 used in the United States was imported from Japan. In 1989, the importation and sale of L-.beta.-3 in the U.S. was halted by the U.S. Food and Drug Administration (FDA) as a result of a highly toxic contaminant that was found in batches of L-.beta.-3 made by a bacterial fermentation process used by one particular Japanese company. To date, the importation of L-.beta.-3 into the U.S. and the sale of all imported L-.beta.-3-containing products has not resumed. L-.beta.-3 is still unavailable to the public because of the difficulty in excluding possible toxic compounds which could be generated in L-.beta.-3 produced by fermentative processes.
Natural L-.beta.-3 is the only substance which will increase brain serotonin in a normal physiological manner. A need exists for natural L-.beta.-3 which can serve as a direct precursor for the synthesis of serotonin in the brain, serve as a source of serotonin which is free of the many side effects encountered with the use of serotonin-enhancing medications, and is obtained in a manner which ensures that no potentially toxic compounds are produced by the microorganism which produces the L-.beta.-3 as a part of its metabolic cycle.